The present invention relates generally to lipoprotein (a), Lp(a) and more particularly to methods and agents to lower its plasma concentrations to achieve therapeutic benefit.
The macromolecule known as lipoprotein (a) or Lp(a), is a complex of low density lipoproteins (LDL), and a hydrophilic glycoprotein that has been given the name apolipoprotein (a), or apo(a). The principal protein of LDL is apo B-100 and apo(a) is attached to the apo B moiety of LDL by a disulfide bond. LDL is the major transporter of cholesterol in human plasma. The physiological function of Lp(a) is unknown.
Apo(a) is not similar in structure to other apolipoproteins but exhibits similarity to another plasma protein called plasminogen. Plasminogen structure includes five tandemly repeated homologous domains called kringles (Kringles I-V), which are pretzel-like structures stabilized by three internal disulfide bridges followed by a protease domain. Kringle structures have been identified in various other proteins such as prothrombin, tissue-type plasminogen activator (t-PA), urokinase and coagulation factor XII (Utermann, SCIENCE, 246:904-910, 905 (1989)). Apo(a) lacks kringles similar to I to III of plasminogen but has multiple copies of the kringle domain similar to the fourth one of plasminogen, and a single copy of a kringle domain similar to the fifth one of plasminogen (kringle-5). Apo(a) also contains a protease domain.
Lp(a) was first identified by Berg in 1963 (Berg, ACTA PATHOL. MICROBIOL. SCAND., 59:369 (1963)) as an antigenic activity associated with the LDL fraction in the plasma of some individuals. Plasma Lp(a) levels vary in different individuals from less than 2 mg/dl to greater than 200 mg/dl. Increased plasma Lp(a) levels are considered to be a risk factor for atherosclerosis, either alone or in conjunction with elevated LDL levels (Kostner et al., CIRCULATION, 80(5):1313-1319 (1989) citing previous investigators). The plasma concentration of Lp(a) and the size of apo(a) are genetically determined (Gavish et al., J. CLIN. INVEST., 84:2021-2027 (1989)).
The discovery of the homology of apo(a) to plasminogen has prompted further investigation as to the role played by Lp(a). Hajjar et al. considered the similarity between the apo(a) component of Lp(a) and plasminogen and investigated the effect that Lp(a) might have on the interaction between plasminogen and the endothelial cell, and found that Lp(a) competed for plasminogen binding sites and appeared to be capable of inhibiting the activation of plasminogen on the surface of endothelial cells by t-PA. This suggests that elevated levels of Lp(a) might impair and inhibit cell surface fibrinolysis and thereby encourage the development of a more prothrombotic environment (Hajjar et al., NATURE, 339(6222):303-305 (1989). It is presently suspected that Lp(a) promotes atherogenesis by promoting thrombotic tendencies and interfering with the metabolism of LDL. These observations taken with the relationship between increased concentrations of Lp(a) and increased cardiovascular risk, have prompted the search for ways by which Lp(a) concentrations may be lowered.
Efforts to lower p(a) levels in plasma have included studies wherein known LDL lowering agents have been administered and observed. Thus, in Kostner et al., supra., HMG CoA Reductase inhibitors such as Simvastatin and Lovastatin as well as other known cholesterol-lowering agents were administered to a test group of patients and plasma samples thereafter were taken and examined. None of the tested agents appeared to lower Lp(a) levels, and, in fact, in some instances, Lp(a) levels appeared to rise, possibly due to stimulation of Lp(a) production. The authors identified only two agents, namely neomycin and niacin, that are known to decrease both LDL and Lp(a) levels. These agents only lower Lp(a) to a limited extent and because of this as well as toxic side effects do not appear to present a viable therapeutic avenue.
A need therefore exists for an effective method and associated agents for decreasing plasma Lp(a) levels.